Tolero Pharmaceuticals Presents Clinical Data for Investigational Agent Alvocidib in Patients with Relapsed Refractory MCL-1-Dependent AML at EHA 2018

SALT LAKE CITY, June 15, 2018 /PRNewswire-USNewswire/ -- Tolero Pharmaceuticals, Inc., a clinical-stage company focused on developing novel therapeutics for hematological and oncological diseases, today announced preliminary data from Zella 201, an ongoing Phase 2 study evaluating the efficacy and safety of alvocidib, a potent CDK9 inhibitor, in combination with cytarabine and mitoxantrone in patients with relapsed or refractory MCL-1-dependent acute myeloid leukemia (AML). Findings are being presented today at the 23^rd Annual Congress of the European Hematology Association (EHA), taking place June 14-17, 2018, in Stockholm, Sweden.

Preliminary data from Stage 1 of the study indicated alvocidib in combination with cytarabine and mitoxantrone has shown encouraging activity in 18 patients with MCL-1-dependent AML, with the majority of patients achieving a complete remission (CR) or complete remission with incomplete recovery (CRi). The study found an overall CR/CRi rate of 61% (n=11) and an overall response rate (ORR, CR/CRi/PR) of 67% (n=12). In patients who were refractory to frontline therapy, CR/CRi rate was 75% (n=6) and ORR was 88% (n=7). Patients that attained a CR/CRi (n=11) experienced a median duration of response of 8.2 months and median overall survival of 10.1 months. In addition, 44% (n=8) of patients proceeded to post-study stem cell transplant (SCT), including 63% (n=5) of previously refractory patients. Adverse events in the study are consistent with those noted in previous studies and include tumor lysis syndrome, sepsis, diarrhea and elevated AST levels.¹

"Our understanding of acute myeloid leukemia is evolving as we deepen our knowledge about the different mechanisms that play a role in the disease," said Joshua F. Zeidner, MD, lead investigator of the Zella 201 study and assistant professor, Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill. "These preliminary results are encouraging as they indicate alvocidib in combination with cytarabine and mitoxantrone may have activity in patients with relapsed and refractory MCL-1-dependent AML."

In the study, a total of 21 patients have been enrolled to date, all of whom have MCL-1 dependency of 40% or higher. To date, 18 patients have been evaluated and 3 patients are pending evaluation. Following the completion of the first stage of the study, the study will move to Stage 2, a randomized Phase 2 expansion comparing the combination of alvocidib, cytarabine and mitoxantrone to cytarabine and mitoxantrone.¹

"We are encouraged by these preliminary Phase 2 data on alvocidib in patients with relapsed and refractory MCL-1-dependent acute myeloid leukemia, which adds to our growing understanding of the potential utility of targeting MCL-1 via CDK9 inhibition," said David J. Bearss, Ph.D., Chief Executive Officer of Tolero Pharmaceuticals, Inc. "We are continuing to progress the Phase 2 clinical program on alvocidib, including the Zella 201 study, and look forward to sharing additional results."

Below are the details for the poster presentation:

    Abstract Title                   Details                 Author
    --------------                   -------                 ------

    Phase II Study Incorporating a
     Novel                           Abstract #PF243         Joshua F. Zeidner,
    BH3-Profiling Biomarker Approach
     of                                                      MD, Lineberger
    Alvocidib Followed by Cytarabine
     and                             June 15, 5:30 to 7 p.m. Comprehensive
    Mitoxantrone in Relapsed/
     Refractory                      CEST                    Cancer Center,
    Acute Myeloid Leukemia (AML)                             University of North
                                     Poster presentation     Carolina, Chapel Hill,
                                                             NC

    ---

About Alvocidib
Alvocidib is an investigational small molecule inhibitor of cyclin-dependent kinase 9 (CDK9) currently being evaluated in a Phase II study, Zella 201 in patients with relapsed or refractory MCL-1-dependent acute myeloid leukemia, AML, in combination with cytarabine and mitoxantrone (NCT02520011). Alvocidib is also being evaluated in Zella 101, a Phase I clinical study evaluating the maximum tolerated dose, safety and clinical activity of alvocidib in combination with (7+3) in newly diagnosed patients with AML (NCT03298984).

About CDK9 Inhibition and MCL-1
MCL-1 is a member of the apoptosis-regulating BCL-2 family of proteins.² In normal function, it is essential for early embryonic development and for the survival of multiple cell lineages, including lymphocytes and hematopoietic stem cells.³ In MCL-1-dependent AML, MCL-1 inhibits apoptosis and sustains the survival of leukemic blasts, which may lead to relapse or resistance to treatment.^2,4 The expression of MCL-1 in leukemic blasts is regulated by cyclin-dependent kinase 9 (CDK9).^5,6 Because of the short half-life of MCL-1 (2-4 hours), the effects of targeting upstream pathways are expected to reduce MCL-1 levels rapidly.⁵ Inhibition of CDK9 has been shown to block MCL-1 transcription, resulting in the rapid downregulation of MCL-1 protein, thus restoring the normal apoptotic regulation.²

About Tolero Pharmaceuticals, Inc.
Tolero Pharmaceuticals is a clinical-stage biopharmaceutical company researching and developing treatments to improve and extend the lives of patients with oncological and hematological diseases. Our diverse pipeline targets important biological drivers of blood disorders to treat leukemias, anemia, and solid tumors, as well as targets of drug resistance and transcriptional control. Tolero Pharmaceuticals is based in the United States and is an indirect, wholly-owned subsidiary of Sumitomo Dainippon Pharma Co., Ltd., a pharmaceutical company based in Japan.

Additional information about the company and its product pipeline can be found at www.toleropharma.com.

Tolero Pharmaceuticals Forward-Looking Statements
This press release contains "forward-looking statements", as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding the research, development and commercialization of pharmaceutical products. The forward-looking statements in this press release are based on management's assumptions and beliefs in light of information presently available, and involve both known and unknown risks and uncertainties, which could cause actual outcomes to differ materially from current expectations. Any forward-looking statements set forth in this press release speak only as of the date of this press release. We do not undertake to update any of these forward-looking statements to reflect events or circumstances that occur after the date hereof. Information concerning pharmaceuticals (including compounds under development) contained within this material is not intended as advertising or medical advice.

References
¹ Zeidner JF, Vigil CE, Lin T, et al. Phase II Study Incorporating A Novel Bh3-Profiling Biomarker Approach Of Alvocidib Followed By Cytarabine And Mitoxantrone In Relapsed/Refractory Acute Myeloid Leukemia (AML). In: European Hematology Association; 2018 June 14-17; Stockholm, Sweden; Abstract PF243.

² Thomas D, Powell JA, Vergez F, et al. Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription. Blood. 2013;122(5):738-748.

³ Perciavalle RM, Opferman JT. Delving deeper: MCL-1's contributions to normal and cancer biology. Trends Cell Biol. 2013;23(1):22-29.

⁴ Glaser SP, Lee EF, Trounson E, et al. Anti-apoptotic Mcl-1 is essential for the development and sustained growth of acute myeloid leukemia. Genes Dev. 2012;26(2):120-125.

⁵ Chen R, Keating MJ, Gandhi V, Plunkett W. Transcription inhibition by flavopiridol: mechanism of chronic lymphocytic leukemia cell death. Blood. 2005;106(7):2513-2519.

⁶ Ocana A, Pandiella A. Targeting oncogenic vulnerabilities in triple negative breast cancer: biological bases and ongoing clinical studies. Oncotarget. 2017;8(13):22218-22234.

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SOURCE Tolero Pharmaceuticals, Inc.